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Mike Russell

Mike Russell Consultants Ltd

• QPs are required to “have an awareness” of investigational medicinal products (IMPs),

and this paper is intended to provide this awareness.

Mike Russell Consultants Ltd;

What is a Clinical Trial?

• An experiment on people
• Controlled by Governments
• Directives and Regulation
• Protects Patient and data integrity
• Declaration of Helsinki

• A clinical trial is an experiment on human beings and is controlled by government.

Principle controls are the Declaration of Helsinki, which is designed to give protection to
the patient, or subject; and Good Clinical Practice, which goes into more detail and
additionally requires integrity of the data produced. GCP overlaps with GMP in certain
areas, particularly packaging and distribution. More topically, clinical trials are governed
by Directives 2001/20/EC, 2003/94/EC and Statutory Instrument 2004 No.1031 which
have now been given the force of law.
• The legal definition of a clinical trial is
• “Any investigation in human subjects intended to discover or verify the clinical,
pharmacological and/or pharmacodynamic effects of an investigational medicinal
product(s), and/or to identify any adverse reactions to an investigational medicinal
product(s) and/or to study the absorption, distribution, metabolism and excretion of an
investigational product(s) with the objective of ascertaining its safety and/or efficacy.

• Every trial is conducted to a protocol

• Approved by Govt.
• Approved by ethics committee
• Lays out conduct of trial
e.g. drug administration, patient selection,
trial design, statistical treatment etc

• Every trial is conducted to a protocol, which sets out everything relevant as to how the
trial is to be performed. This protocol includes the patient selection criteria, the centres
involved, the design of the trial, statistical treatment, patient consent, drug
administration, etc. The protocol has to be approved both by the competent authority and
an ethics committee. The ethics committee should judge whether the data to be obtained
by the trial is proportional to the risk and inconvenience to the patient.
Clinical Trial Phases

• Spectrum
• Phase I – human volunteers, small
numbers, dose and safety
• Phase II – small numbers of patients,
safety and efficacy
• Phase III – larger numbers of patients,
safety and efficacy
• Phase IV – post marketing surveillance.

• Trials are classed as Phase I, II, III or IV. These classifications are for convenience only
and, in fact, merge into each other to form a spectrum.
• Phase I trials are usually conducted in healthy volunteers to obtain data on safety and
dosage. Numbers are small, of the order of 20 people. They are usually simple, open
label but can be very complex and randomised with double blinding. FDA is relaxed
about production, except for steriles, and will not inspect except ‘for cause’
• Phase II trials are in patients to discover efficacy and safety; numbers are in the
• Phase III trials are conducted in larger numbers again, to prove safety and efficacy using
the proposed market formulation. These may also have a sub-set of trials called “pivotal”
i.e. that (those) on which the submission is primarily based.
• Phase IV is properly not a trial at all, but refers to immediate post marketing surveillance
to monitor for unexpected adverse reactions to be found in a wider population.
Clinical Trial Design

• Placebo controlled
• Comparator controlled
• Open
• Single blind
• Double blind
• Ascending dose
• Crossover (+/- washout)
• Randomisation

• These vary from extremely simple (e.g. open studies) to extremely complex. The
complexity arises from the data to be obtained and the phase of the study.
• Placebo controlled studies are those where the new active is compared to a non-active
control. These are becoming less ethically acceptable, but are the best science.
• Comparator controlled trials are those where the new active is compared to an existing,
available pharmaceutical.
• Open studies are those where both the patient and doctor know who is getting the active
drug and who the placebo/comparator.
• Single blind studies are where the doctor knows who is receiving the active, but the
patient doesn’t. Obviously, these two designs are open to subjective bias and are thus
rare, although more common in Phase I.
• Double blind studies are when neither patient nor doctor knows who is receiving the
active and placebo/comparator. The effectiveness of blinding must be addressed in the
specification. Blinding may be accomplished by e.g. putting a tablet into a capsule,
emptying a capsule into a syrup etc.
• To avoid bias in subject selection, most trials are randomised so that allocation to active
or placebo/comparator is statistically valid and not biased.
• Other complications may be
• ascending dose,
• crossover between active and placebo/comparator, with or without a placebo washout.
GMP issues - 1

• GMPs are different – Annex 13

• Placebos and comparators are IMPs

– Placebos have to be non-active and identical

• These are allowed to be different in Annex 13.

• Placebos are IMPs and must be demonstrated to be placebos.
GMP issues - 2

• Comparator issues:
– Stability
– Reference substances
– Assay
– Shelf life
– Recalls

• Comparators are IMPs. This gives issues of

• stability if manipulated,
• assay,
• reference standards
• shelf lives,
• recalls.
• Imports from third countries must be tested on import.
GMP issues – 3
Manufacture and Validation

• Every batch is different

• Change control is essential
• History difficult
• Validation appropriate to phase
• Validate patient safety processes
• Qualify equipment

• Every batch can be different. Change control is essential. History is scarce, difficult to
find and may be anecdotal.
• Validation has to be done to a level appropriate to the phase of study. For example, it is
unlikely that three batches will be produced until just prior to marketing. However,
equipment qualification is expected, especially of patient safety critical equipment, such
as autoclaves.
GMP issues – 4

• Ad hoc specifications
• Impurities
• Organoleptic tests
• Validated assay?
• Reference substances?
• History

• Ad hoc specifications are the norm, based on educated guesses. Blinding is required to
be part of the specification and should include organoleptic tests – safety issues?
• Reference substances are likely to be in an early stage of development, and impurity
levels and substances involved unlikely to be well defined.
GMP issues – 5

• Double blinding – breaks all rules –

everything looks the same

• Manipulation and blinding of comparator

• If double blinding is required, then every unit must be identical to an observer. This gives
obvious risks of cross contamination.
• There are also the issues of manipulation e.g. grinding down a tablet to fill into capsules
GMP issues – 6

• Multi-product plant

• Incompletely characterised chemicals

• Manual cleaning

• Double problems of unknown actives and comparators in a multi-product facility which is

unlikely to have automated cleaning of equipment.
GMP issues – 7

• Overlap with GCP

• Cold chain
• Addressee
• Security within hospitals

• Maintaining chain of responsibility is necessary, together with security, especially within

a hospital. Inside the hospital, these are usually the responsibility of the clinical trial
monitor but the responsibility has to be clarifies and documented.
• Cold storage products have to be particularly monitored. Fridges are rarely controlled in
hospitals and freezers, especially below –20C, are rare.
GMP issues – 8

• Each BMR is a one off

• Specifications are embryonic or general
and based on “prior knowledge”!
• Reviews essential but rare
• Change control can be rudimentary

• Each BMR is a one off and therefore has to be approved against the Product
Specification File. The changes made, either during production, or subsequently, to the
next batch have to be captured so that the continuity of the product is demonstrated to
be maintained. There also should be a formal review to establish that changes made still
reflect submitted data and regulatory committements.
GMP issues – 9

• Highly educated

• Development scientists

• GMP is a restriction

• Personnel are generally highly educated (but not necessarily trained) and recruited as
scientists to develop the IMP and/or process. GMP can be seen as a restriction.
However, it is expected that the level of GMP increases with knowledge and
development. This should be merely(!) Good Science. It is really the QP who has to
decide on and implement the level required.
Overlap with GCP

• Requires monitoring of packaging,

randomisation, distribution, storage, usage,

• Requires system to ensure both regulatory

and technical approval – green lights

• It is also a requirement of GCP that monitoring of packaging (especially randomisation)

and distribution and storage is carried out. There is also a GCP requirement to monitor
and record all returns and their destruction.
• Before administration of the IMP (shipping?), there must be both regulatory approval and
technical approval (QP release). These are known as ‘green lights!’
Joys and Sorrows

• Pressures to release high

• Involvement – people, patients, process

• Uses lot of knowledge and judgment

• Pressures to release are high, higher than in the commercial world. The effect on
company finance can be enormous.
• The QP is very much closer to the patient who can be identified as a real person.
• The QP gets to use more knowledge and judgement than is usual in the commercial
world – every batch is different!!
Thank you!

Mike Russell Consultants Ltd